Methylmalonyl isomerase

Carbonic Anhydrase Cytochromes Cytochrome P-450 Aldehyde Oxidase Catalase, Peroxidase Hydrogenase Methylmalonyl Isomerase Kinase... 

Kellermeyer RW, Allen SHG, Stjemholm R and Wood HG (1964) Methylmalonyl isomerase. IV. Purification and properties of the enzyme from propionibacteria. J Biol Chem 239 2562-2569... 

Methylmalonyl isomerase, the enzyme that converts methylmalonyl CoA to succinyl CoA, was studied by Beck el ai. 9 ). Methylmalonyl CoA is the required substrate. Evidence was obtiuned that the reaction is reversible. The isomerase was found to be present in a variety of tissues liver, heart, and kidney being the most active. 

It has recently been established that a vitamin Bn derivative is the coenzyme of methylmalonyl isomerase (105a, 106). 

Adenosylcobalamin (coenzyme 812) carries a covalently bound adenosyl residue at the metal atom. This is a coenzyme of various isomerases, which catalyze rearrangements following a radical mechanism. The radical arises here through homolytic cleavage of the bond between the metal and the adenosyl group. The most important reaction of this type in animal metabolism is the rearrangement of methylmalonyl-CoAto form succinyl-CoA, which completes the breakdown of odd-numbered fatty acids and of the branched amino acids valine and isoleucine (see pp. 166 and 414). 

Oxidation of unsaturated fatty acids requires two additional enzymes enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase. Odd-number fatty acids are oxidized by the /3-oxidation pathway to yield acetyl-CoA and a molecule of propionyl-CoA This is carboxylated to methylmalonyl-CoA, which is isomerized to succinyl-CoA in a reaction catalyzed by methylmalonyl-CoA mutase, an enzyme requiring coenzyme B12. 

Propionyl CoA then adds on CO2 Four carbons so far, unlike sugar The carboxylase using an ATP too It costs quite a lot to make sugar Methylmalonyl CoA thus having been made An isomerase comes along, places to trade (No ATP needed, bond energy s paid)... 

Methylmalonic aciduria Methylmalonyl-CoA isomerase or vitamin Bu coensyme Methylmalonic acid (4 glydne) Methylmalonic acid Metbylmalmiic add increased in CSF, keto-nuria, protdn intolerance Coma, extensOT spasna. retarded devdopment, metabolic addosis (vitamin Bu treats ment) Chromatography Aeetest sticks (01, R9. Rll, R12. S41. S53)... 

Isomerases that are dependent on coenzyme B12 constitute the largest subfamily of Bi2 enzymes and are components of a number of fermentative pathways in microbes [10, 11]. A single member of this group of enzymes, methylmalonyl-CoA mutase, is found in both bacteria and in mammals where it is a mitochondrial enzyme involved in the catabolism of odd-chain fatty acids, branched chain amino... 

Coenzyme B12 is involved in wframolecular alkyl group transfer in the methylmalonyl-CoA isomerase and glutamate mutase reactions. (see reference I4), both of which may be schematically represented as ... 

The propionyl CoA carboxylation is another reaction in which the energy required to synthesize a car-bon-to-carbon bond is provided by ATP. Thus, the free energy of the pyrophosphate bond is transferred to CO2, which forms an N-carboxy bond with the biotin enzyme complex. Some of the molecular details of the propionyl carboxylation reaction are presented in Fig. 1-27. The isomerization of methylmalonyl CoA to succinyl CoA also involves vitamin B12. At first it was demonstrated that the activity of the isomerase was considerably decreased in the liver of vitamin B 12-deficient rats. Later the stimulating effect of 5,6-dimethylbenzimidazole carbamide coenzyme was demonstrated with partially purified preparations of the liver enzyme. The methylmalonate CoA-isomerase complex purified from sheep liver has been divided into two different protein fractions, one with isomerase and the other racemase activity. The isomerase acts on only one of the enantiomorphs of methylmalonyl CoA, but the absolute formula of the enantiomorph that serves as substrate for the isomerase is unknown. A racemase catalyzes the conversion of the alternate enantiomorph to the substrate of the isomerase. 

The metabolic role of many minerals and vitamins is as prosthetic groups or coenzymes in different enzyme systems. Consequently, mineral and vitamin deficiencies can cause a breakdown of the processing system and precipitate metabolic disease. For example, methylmalonyl-CoA isomerase (see p. 203) is an important vitamin Bi2-dependent enzyme in the gluconeogenic pathway. A deficiency of vitamin B12 (or cobalt) may reduce enzyme activity, decrease the efficiency of glucose synthesis and predispose the animal to ketosis. Similarly, ceruloplasmin is a copper-dependent enzyme responsible for releasing iron from cells into blood plasma. A copper deficiency may reduce ceruloplasmin activity, decrease the efficiency of iron utilisation for haemoglobin synthesis and predispose the animal to anaemia. 

Methylmalonyl-CoA mutase (isomerase). Methylmalonyl-CoA mutase catalyzes the interconversion of succinyl-CoA and methylmalonyl-CoA(b), the reaction (reaction 4) that plays an important role in the transformation of pyruvate to propionate in propionibacteria. The isomerization reaction consists in splitting the C1-C2 bond and an intramolecular transfer of the whole thioester group to C3 with a simultaneous transfer of H in the opposite direction (from C3 to C2) ... 

Umlagerung von Methylmalonyl-CoA in Succinyl-CoA. HI. Reinigung und Eigenschaften der Methylmalonyl-CoA Isomerase. Biochem J 336 77-98 Owais WM and Kleinhofs A (1988) Metabolic activation of the mutagen azide in biological systems. MutatRes 197 313-323... 

Finally, it should be noted that coenzyme B g would probably have been discovered by Beck et during their studies of the conversion of methylmalonyl-CoA to succinyl-CoA by the sheep kidney mutase (isomerase) were it not for the fact that this enzyme binds the coenzyme very tightly in such a way that it is not susceptible to inactivation by light. Because of these properties they were unable to obtain a coenzyme-free mutase and so concluded that the reaction probably has no cofactor requirement. 

Carboxylation of propionyl-CoA leads to the formation of D(5)-methyl-malonyl-CoA. D-Methylmalonyl-CoA is converted by methylmalonyl-CoA racemase (EC 5.1.99.1) into the L(/ )-isomer which is in turn converted into succinyl-CoA by the vitamin B 12-dependent methylmalonyl-CoA mutase (EC 5.4.99.2) (formerly isomerase), the succinyl-CoA subsequently entering the tricarboxylic acid cycle. 

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